This project is based on our recent finding that high expression of Human Germinal center Associated Lymphoma (HGAL) - a new gene that we recently cloned and characterized - is an independent predictor of prolonged survival of diffuse large B cell lymphoma (DLBCL) patients. HGAL contains an immunoreceptor tyrosine-based activation motif (ITAM) suggesting a function in signal transduction. HGAL is an IL-4 inducible gene expressed at high levels only in germinal center derived lymphomas and germinal center lymphocytes, especially centroblasts, characterized by high rates of proliferation and apoptosis. These observations suggest that the better survival of patients with high HGAL-content tumors may be attributed to a specific, function of this gene in these processes. However, our additional interesting finding is that BCL6 and FN1- both of which are IL-4 inducible genes are also independent predictors of DLBCL patients' survival. Since high expression of each of these IL-4 inducible genes correlates with prolonged survival, this raises the possibility that high HGAL expression may be a marker of specific IL-4 effects that predicate the good prognosis of these tumors. Indeed, our preliminary data suggest that EL-4 has different effects on signaling, gene expression and proliferation in high-HGAL versus low-HGAL DLBCL cell lines derived from tumors. Therefore the major goal of this project is to establish tumor-related HGAL function and to determine whether HGAL expression directly predisposes to improved DLBCL survival or is a marker of IL-4 effects on lymphoma. In this project we will: 1). determine effects of HGAL on cell proliferation and apoptosis, 2). determine the prognostic and diagnostic significance of HGAL protein expression in DLBCL and other lymphomas, 3). determine the mechanisms underlying cell cycle arrest induced by IL-4 in the low-HGAL DLBCL cells, 4). extend our observations on effects of IL-4 on proliferation and apoptosis of DLBCL cell lines to primary high-HGAL and Iow-HGAL expressing DLBCL tumors. These findings should establish an immunohistochemical prognostic marker for the most common type of lymphoma - DLBCL that will be used in clinical practice and will add to the prognostic power of the current clinical prognostic indexes. Furthermore, these studies should determine the potential function of HGAL in germinal center lymphocytes and germinal center derived lymphomas and the potential role of IL-4 in distinct DLBCL subsets. These mechanistic studies may provide approaches for new therapeutic strategies.